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Gut. 2019 May 10. pii: gutjnl-2019-318382. doi: 10.1136/gutjnl-2019-318382. [Epub ahead of print]

Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis.

Author information

1
Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
2
Department of Hepatology/Gastroenterology, Charité University Medical Center, Berlin, Germany.
3
IZKF Genomics Facility, University Hospital Aachen, Aachen, Germany.
4
Institute of Computational Genomics, RWTH-University Hospital Aachen, Aachen, Germany.
5
Department of Intensive and Intermediate Care, University Hospital Aachen, Aachen, Germany.
6
Department of Medicine III, University Hospital Aachen, Aachen, Germany.
7
Institute of Computational Genomics, University Hospital Aachen, Aachen, Germany.

Abstract

OBJECTIVE:

Bone marrow-derived myeloid cells accumulate in the liver as monocytes and macrophages during the progression of obesity-related non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). Myeloid cells comprise heterogeneous subsets, and dietary overnutrition may affect macrophages in the liver and bone marrow. We therefore aimed at characterising in depth the functional adaptations of myeloid cells in fatty liver.

DESIGN:

We employed single-cell RNA sequencing to comprehensively assess the heterogeneity of myeloid cells in the liver and bone marrow during NAFLD, by analysing C57BL/6 mice fed with a high-fat, high-sugar, high-cholesterol 'Western diet' for 16 weeks. We also characterised NAFLD-driven functional adaptations of macrophages in vitro and their functional relevance during steatohepatitis in vivo.

RESULTS:

Single-cell RNA sequencing identified distinct myeloid cell clusters in the liver and bone marrow. In both compartments, monocyte-derived populations were largely expanded in NASH-affected mice. Importantly, the liver myeloid compartment adapted a unique inflammatory phenotype during NAFLD progression, exemplarily characterised by downregulated inflammatory calprotectin (S100A8/A9) in macrophage and dendritic cell subsets. This distinctive gene signature was also found in their bone marrow precursors. The NASH myeloid phenotype was principally recapitulated by in vitro exposure of bone marrow-derived macrophages with fatty acids, depended on toll-like receptor 4 signalling and defined a characteristic response pattern to lipopolysaccharide stimulation. This imprinted and stable NASH myeloid immune phenotype functionally determined inflammatory responses following acute liver injury (acetaminophen poisoning) in vivo.

CONCLUSION:

Liver myeloid leucocytes and their bone marrow precursors adapt a common and functionally relevant inflammatory signature during NAFLD progression.

KEYWORDS:

NAFLD; fatty acids; inflammation; liver; macrophages; monocytes

PMID:
31076404
DOI:
10.1136/gutjnl-2019-318382

Conflict of interest statement

Competing interests: Work in the lab of FT has received research funding from Allergan, Galapagos, Inventiva and Bristol Myers Squibb.

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